tbuckley/cabot-search huggingface dataset:
Abstract 5004: Integrative quality control of cancer somatic mutations with CaMutQC
Authors: Xin Wang, Jian Ren, Qi Zhao
Journal: Cancer Research (2022)

Abstract The quality control of cancer somatic mutations is an essential step for eliminating false positive mutations from technical bias, and selecting key mutation candidates plays a crucial role in both downstream translation research and personal medical decisions. Existing tools, with complicated parameters and changeable filtering standards, may not be suitable specifically for cancer somatic mutations. In addition, previous genomic studies usually adopted different filtering criteria for processing raw sequencing datasets, which greatly restricts the efficiency of integrative exploration for cancer genomics. In this study, we presented CaMutQC, a heuristic cancer somatic mutations (CAMs) quality control and filtration package for cancer genomic studies. CaMutQC provides two schemes, including filtration of false positive mutations generated by technical issues, and the screening of candidate cancer somatic mutations from single or multiple VEP-annotated files in VCF format. Specifically, for quality control, instead of directly discarding CAMs that failed to meet the thresholds of parameters collected from classic studies, CaMutQC labels them with customized tags to represent the filtering type, enabling portable subsequent analyses. And a vivid and well-structured filter report is generated after filtration or selection. In addition, we proved by applying an updated mutation QC strategy, which takes the union of CaMutQC-filtered cancer variants from multiple variant callers (eg. MuTect, MuSE and VarScan2) on published datasets that, CaMutQC can not only reduce the false positive CAMS, but also greatly rescue the false negative CAMS from each single caller or the overlap of multiple tools. In summary, in this study, for the first time, we systematically implemented the parameters and criteria of CAMs quality control from published studies into the CaMutQC package, which we believe it would be a valuable tool for cancer genomic research. CaMutQC is implemented in R and is available at https://github.com/likelet/CaMutQC under the GPL-v3 license. Citation Format: Xin Wang, Jian Ren, Qi Zhao. Integrative quality control of cancer somatic mutations with CaMutQC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5004.
Abstract 6099: Differential gene expression related to TMPRSS2-ERG fusion, CDK12, RB1, TP53, AR and ZEB1 based on transcriptomic analysis of the TCGA PRAD cohort
Authors: William Lautert-Dutra, Camila Morais Melo, Luiz Paulo Chaves, André Luiz Caliari, Francisco Cesar Souza Silva, Jeremy Andrew Squire
Journal: Cancer Research (2022)

Abstract Prostate Cancer (PCa) is considered an immunologically excluded tumor, unable to generate an effective T-cell response against cancer cells. Inactivating mutations of the PTEN tumor suppressor are one of the most common events in human malignancies that contribute to tumorigenesis by affecting many cancer Hallmark pathways. The CDK12, RB1, TP53, AR and ZEB1 genes have been variously implicated in pathways of PCa progression and immune evasion. Here, we present a comprehensive analysis of The Cancer Genome Atlas derived PCa cohort (n=488, 96 homozygous and 64 hemizygous PTEN loss). Differential gene expression (DGE) and pathway enrichment analysis were performed for all five genes using the DESeq2 tool from the Bioconductor package for R. All comparisons were designed to compensate for gene expression changes caused by PTEN loss (Table 1). Functional pathway analysis showed that fusion positive samples presented several downregulated pathways, including leukocyte mediated cytotoxicity, IFN type I response and IFN-γ production. AR high presented upregulation of pathways such as DNA replication and chromatin remodeling, while AR low presented upregulation of pathways such as T cell activation and lymphocyte proliferation. ZEB1 high presented a wide range of enriched pathways, including upregulation of mesenchymal cell differentiation and T cell activation. CDK12-Hom group exhibited upregulation of T cell activation, T cell differentiation and IFN-γ production. TP53 mutation revealed upregulation of various pathways including DNA replication and cell division. RB1 loss showed enrichment of pathways such as T cell activation and lymphocyte activation. Our analysis showed that variation in these five genes can promote gene expression changes associated with clinically relevant pathways independently of PTEN and that AR, CDK12, TMPRSS2-ERG fusion, ZEB1 and RB1 status are potential biomarkers for immunotherapy response. Table 1. Differential genes expression results summary Comparison # of upregulated (LFC&amp;gt;0) # of downregulated (LFC&amp;lt;0) Fusion positive vs. Fusion negative 2997 5418 AR low vs. AR medium 4133 4167 AR high vs. AR medium 4365 2589 CDK12-Hom vs. CDK12 WT 2416 713 CDK12-Hem vs. CDK12 WT 704 387 ZEB1 high vs. ZEB1 normal 6439 6792 RB1 mut vs. RB1 WT 78 335 TP53 mut vs. TP43 WT 859 1193 Citation Format: William Lautert-Dutra, Camila Morais Melo, Luiz Paulo Chaves, André Luiz Caliari, Francisco Cesar Souza Silva, Jeremy Andrew Squire. Differential gene expression related to TMPRSS2-ERG fusion, CDK12, RB1, TP53, AR and ZEB1 based on transcriptomic analysis of the TCGA PRAD cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6099.
Abstract 5619: Co-occurrence of<i>Lactobacillus</i>and<i>Candida sp.</i>in periodontal disease severity suggests cancer-related dysbiosis
Authors: Kimil T. Acosta-Pagán, Filipa Godoy-Vitorino, Bejamín Bolaños-Rosero, Ana P. Ortíz, Carla Oramas-Sepúlveda, Cynthia M. Pérez, José A. Vivaldi-Oliver, Josué Pérez-Santiago, Maira Castañeda-Avila
Journal: Cancer Research (2022)

Abstract Introduction: Microbiota plays an essential role in the oral cavity and oral dysbiosis, leading to inflammatory diseases such as periodontitis. Periodontal disease is associated with a two-fold increase in the risk of oral cancer; thus, evaluating polymicrobial associations across a gradient of periodontitis will help understand the microbial processes that could influence cancer development. We aimed to study the association of oral bacteria and fungi linked to high-risk behavior and periodontal disease. Methods: This cross-sectional study recruited individuals aged 21 to 49 from sexually transmitted infection clinics in Puerto Rico. A total of 88 participants underwent a full-mouth periodontal examination following the NHANES protocol. Periodontal severity was defined according to the CDC/AAP. Saliva was collected for genomic DNA extraction, and downstream 16S V4 and ITS-2 genes were amplified, sequenced, and analyzed with standard bioinformatics pipelines. Results: Nearly 29% of individuals had some degree of periodontal disease. Bacterial community analyses revealed differences in both composition and diversity as the periodontal disease progressed. The predominance of Prevotella and Veillonella in the salivary microbiota was attributed to periodontal conditions with low levels of Lactobacillus in patients with severe disease. In contrast, the predominance of Neisseria was related to healthy participants. Fungal communities changed in composition with disease severity, including the dominance of Candida tropicalis. Co-occurrence analyses revealed that Lactobacillus co-occurred with Candida dubliniensis, C. tropicalis, and Saccharomyces cerevisiae in individuals with periodontal disease. Conclusion: Co-occurrence patterns of bacteria and fungi changed from participants with no disease to periodontal severity. Lactobacillus has been identified in caries, xerostomia, and saliva of HPV-positive head and neck cancer patients. This study is the first to report the co-occurrence of this Lactobacillus with oral candidiasis in periodontal severity. We expect that these biofilms induce inflammation in periodontal pockets while also making them more resistant to treatments. Citation Format: Kimil T. Acosta-Pagán, Filipa Godoy-Vitorino, Bejamín Bolaños-Rosero, Ana P. Ortíz, Carla Oramas-Sepúlveda, Cynthia M. Pérez, José A. Vivaldi-Oliver, Josué Pérez-Santiago, Maira Castañeda-Avila. Co-occurrence ofLactobacillusandCandida sp.in periodontal disease severity suggests cancer-related dysbiosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5619.
Abstract 2962: The oncogenic role of epigenetic factor, SNF2L in PCa
Authors: LaKendria K. Brown, Guoliang Li, Thanigaivelan Kanagasabai, Zhenbang Chen
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is the second-leading cause of cancer mortality in the United States and is the most commonly diagnosed malignancy in African American men. Epigenetic regulation including chromatin remodeling plays a crucial role in the development and progression of many human diseases such as cancers. Epigenetic alterations contribute to the development and progression of PCa. These alterations may cause drug resistance to readily available treatment options for human cancers including PCa. Nucleosome-remodeling factor (NURF) consists of bromodomain-PHD finger transcription factor (BPTF), sucrose non-fermenting-2-like (SNF2L), and pRBAP46/48, controls the chromatin remodeling machinery. One of NURF’s major function is to regulate histone modifications and gene expression. Epigenetic factor, SNF2L, serves as the energy transducing subunit in NURF and is encoded by the SMARCA1 gene. SNF2L is a ubiquitously expressed transcription activator and its elevation is associated with cancer development. However, the role of SNF2L on PCa progression is still elusive. Therefore, there are unmet needs to understand the role of SNF2L in PCa in order to develop effective therapeutic approaches of controlling this malignancy. The objective of this project is to assess the impact of SNF2L loss on PCa progression. We hypothesized that SNF2L knockout (KO) will inhibit the proliferation of androgen-sensitive and castration-resistant PCa cells and targeting SNF2L or SMARCA-1 gene may be beneficial for controlling cancer progression. We have generated SNF2L KO PCa cells with CRISPR-Cas9 technology and inhibited SMARCA-1 gene via transient transfection application. Our results showed that SNF2L loss resulted in a reduced proliferation and altered morphology of PCa cells. SNF2L KO destabilizes the NURF complex and impairs chromatin remodeling and histone modifications for cell growth and survival. Thereby, targeting SNF2L may serve as a novel therapeutic regime in PCa control. Citation Format: LaKendria K. Brown, Guoliang Li, Thanigaivelan Kanagasabai, Zhenbang Chen. The oncogenic role of epigenetic factor, SNF2L in PCa [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2962.
Proteomic Mapping and Targeting of Mitotic Pericentriolar Material in Tumors Bearing Centrosome Amplification
Authors: Bingteng Xie, Yang Pu, Fan Yang, Wei Chen, Wei Yue, Jihong Ma, Na Zhang, Yuening Jiang, Jiegen Wu, Yihan Lin, Xin Liang, Chu Wang, Peng Zou, Mo Li
Journal: Cancer Research (2022)

Abstract Recent work has made it clear that pericentriolar material (PCM), the matrix of proteins surrounding centrioles, contributes to most functions of centrosomes. Given the occurrence of centrosome amplification in most solid tumors and the unconventional survival of these tumor cells, it is tempting to hypothesize that gel-like mitotic PCM would cluster extra centrosomes to defend against mitotic errors and increase tumor cell survival. However, because PCM lacks an encompassing membrane, is highly dynamic, and is physically connected to centrioles, few methods can decode the components of this microscale matrix. In this study, we took advantage of differential labeling between two sets of APEX2-centrosome reactions to design a strategy for acquiring the PCM proteome in living undisturbed cells without synchronization treatment, which identified 392 PCM proteins. Localization of ubiquitination promotion proteins away from PCM was a predominant mechanism to maintain the large size of PCM for centrosome clustering during mitosis in cancer cells. Depletion of PCM gene kinesin family member 20A (KIF20A) caused centrosome clustering failure and apoptosis in cancer cells in vitro and in vivo. Thus, our study suggests a strategy for targeting a wide range of tumors exhibiting centrosome amplification and provides a proteomic resource for future mining of PCM proteins. Significance: This study identifies the proteome of pericentriolar material and reveals therapeutic vulnerabilities in tumors bearing centrosome amplification.
Abstract 2318: Real-time quantitative PCR based analysis of transcriptional effects of CDK8/Cyclin C inhibitors
Authors: Laura M. Jordt, Frank Totzke, Joachim Lauterwasser, Jan E. Ehlert, Koen Hekking, Bas Aerts, Cynthia Obodozie, Holger Weber, Gerhard Müller, Michael H. Kubbutat
Journal: Cancer Research (2022)

Abstract CDK8 has been identified as being frequently upregulated in various types of human cancer such as colorectal cancer, certain sub-types of breast cancer and acute myeloid leukemia. In different tumor cell lines RNA interference mediated knockdown of CDK8 results in significant inhibition of tumor cell growth in vitro and in vivo. CDK8, therefore, represents an interesting target for the development of novel anti-cancer drugs. Various compounds targeting CDK8/Cyclin C with high potency in low nanomolar range have been reported. These compounds differ with respect to their binding modes, but all of them show high potency in biochemical assays, inhibition of tumor cell growth, and for many in vivo activities in different tumor cell xenograft models have been demonstrated. CDK8 binds to Cyclin C resulting in the active protein kinases complex. CDK8/Cyclin C interacts with MED12 and MED13, two proteins that regulate CDK8/Cyclin C activity and its interaction with the mediator complex. Mediator consists of 26 subunits and the interaction of the CDK8/Cyclin C/MED12/Med13 complex with mediator enables CDK8/Cyclin C to regulate gene transcription via C-terminal phosphorylation of RNA-polymerase II. This mechanism mediates an indirect regulation of transcription factors such as ß-catenin. In addition of its function via phosphorylation of RNA-polymerase II, CDK8/Cyclin C can also directly regulate the activity of transcription factors by phosphorylation. Best known examples are STAT1 and STAT5 which are phosphorylated by CDK8/Cyclin C on serine 727 and Serine 726, respectively. Recent data indicates that mutations of MED12 can result in a reduced sensitivity of CDK8/Cyclin C towards certain published CDK8/Cyclin C inhibitor in a cellular context. In this study we performed real-time quantitative PCR (qPCR) analyses to characterize the effect of different type I and type II CDK8/Cyclin C inhibitors on the cellular expression of selected genes controlled by two CDK8/Cyclin C dependent pathways, namely the WNT/ß-catenin- and the STAT-pathway. Furthermore, results of qPCR analyses of tumors derived from human xenograft in vivo models treated with type I and type II CDK8/Cyclin C inhibitors will be presented. Citation Format: Laura M. Jordt, Frank Totzke, Joachim Lauterwasser, Jan E. Ehlert, Koen Hekking, Bas Aerts, Cynthia Obodozie, Holger Weber, Gerhard Müller, Michael H. Kubbutat. Real-time quantitative PCR based analysis of transcriptional effects of CDK8/Cyclin C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2318.
Abstract LB535: A novel IL12-based immunocytokine targeting fibroblast activation protein (FAP) for the treatment of cancer
Authors: Lisa Nadal, Frederik Peissert, Abdullah Elsayed, Chiara Libbra, Dario Neri, Roberto De Luca
Journal: Cancer Research (2022)

Abstract Immunocytokines, which consist of the fusion of cytokines to tumor targeting antibodies, represent a novel class of biopharmaceuticals that have great potential for cancer treatment. The use of these products improves the efficacy of the delivered drug by reducing related side effects and significantly enhances the therapeutic index of the payload. Over the past years, nuclear medicine studies have validated the Fibroblast Activation Protein (FAP) as a pantumoral antigen, with more than 28 different cancer types successfully imaged in patients. Since FAP is mostly undetectable in healthy organs, it has been considered as an attractive target for both imaging and therapeutic applications. For this reason, here we describe the generation of a novel fully human monoclonal antibody targeting FAP. The antibody was isolated from a synthetic antibody phage display library and its tumor recognition properties were validated by immunofluorescence performed on a commercial tissue microarray as well as on freshly frozen colon cancer biopsies from human patients. An ex vivo biodistribution analysis in mice confirmed the ability of anti-FAP in IgG1 format to selectively localize to solid tumors while sparing healthy organs. Furthermore, Pharmacokinetics (PK) studies in Cynomolgus Monkey showed no sink effects at early time points and a slow clearance from bloodstream as expected for IgG1 antibodies. Encouraged by these results, an antibody cytokine fusion (mIL12-FAP) based on the novel anti-FAP antibody was generated and characterized in vitro and in vivo, showing activation of the immune system both in immunocompetent and immunodeficient mouse models bearing FAP-positive tumors. mIL12-FAP exhibited strong anticancer activity in mice bearing CT26-FAP colon carcinomas which could be boosted by the combination with immune checkpoint inhibitors, leading to durable cancer eradication. The targeted delivery of mIL12 to the tumor microenvironment increased the infiltrate of tumor-specific lymphocytes and Natural Killer (NK) cells as compared to the control group without apparent evidence of toxicity. Citation Format: Lisa Nadal, Frederik Peissert, Abdullah Elsayed, Chiara Libbra, Dario Neri, Roberto De Luca. A novel IL12-based immunocytokine targeting fibroblast activation protein (FAP) for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB535.
Improved Efficacy of Tafasitamab plus Lenalidomide versus Systemic Therapies for Relapsed/Refractory DLBCL: RE-MIND2, an Observational Retrospective Matched Cohort Study
Authors: Grzegorz S. Nowakowski, Dok Hyun Yoon, Anthea Peters, Patrizia Mondello, Erel Joffe, Isabelle Fleury, Richard Greil, Matthew Ku, Reinhard Marks, Kibum Kim, Pier Luigi Zinzani, Judith Trotman, Dan Huang, Eva E. Waltl, Mark Winderlich, Nuwan C. Kurukulasuriya, Sumeet Ambarkhane, Georg Hess, Gilles Salles
Journal: Clinical Cancer Research (2022)

Purpose: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes. Results: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R­GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P &amp;lt; 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). Conclusions: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908
Abstract 2990: Role of CCR6-CCL20 chemokine axis in colon cancer
Authors: Briana A. Brock, Shailesh Singh, Hina A. Mir
Journal: Cancer Research (2022)

Abstract Colon cancer remains the third leading cause of cancer-related deaths because chemotherapeutics currently offered to treat early, and advanced colon cancer fail to achieve optimal clinical response. Therefore, development of more efficacious treatment option is crucial to improve clinical outcomes. We have used TCGA and CPTAC analysis from UALCAN data base for the expression of CCR6 and CCL20 in colon cancer tissue compared to adjacent normal. RT-qPCR and proteomics approach were used for analysis of CCR6 and CCL20 expression in colon cancer cell lines. Our data shows higher expression of CCR6 and its ligand CCL20 in colon cancer tissue and cell lines. We further investigated involvement of CCR6/CCL20 on therapeutic response of 5-Fluorouracil and Oxaliplatin commonly used to treat colon cancer. Our data suggest that colon cancer cell lines respond poorly to 5-Fluorouracil and Oxaliplatin when treated with CCL20 and blocking CCR6 with anti-CCR6 improves cytotoxic effect of 5-Fluorouracil and Oxaliplatin. Poor response to chemotherapeutic after CCR6 activation was primarily due to activation molecular and cellular phenotypes and alteration in cell cycle. In conclusion, our data suggest that CCR6/CCL20 promotes colon cancer progression and CCR6-mediates signals contributed to poor response to conventional therapeutic such as 5-Fluorouracil and Oxaliplatin. Hence, targeting CCR6 in early stage will prevent metastasis, enhance therapeutic efficacy and reduce toxicity and will be a promising approach to improve clinical outcome. Citation Format: Briana A. Brock, Shailesh Singh, Hina A. Mir. Role of CCR6-CCL20 chemokine axis in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2990.